The demise of pancreatic islet insulin-secreting ? cells in diabetes has a neuronal component. Therefore, understanding the biology underlying the neuronal control of islet ? cells will unravel information that can be leveraged to develop neuromodulation-based methods to enhance functional ?-cell mass in individuals with diabetes. The pancreas receives a generous supply of efferent parasympathetic and sympathetic neurons and afferent sensory neurons. While the effect of efferent neurons in islet ? cells is well documented, the role of sensory neurons is largely unknown. The pancreatic sensory neurons emanate from the vagal and thoracic spinal nerves with cell bodies lying in the nodose ganglia (NG) and dorsal root ganglia (DRG), respectively. Using chemical and surgical denervation models, we demonstrated that ablation of a subset of DRG pancreas-projecting sensory neurons enhanced glucose-stimulated insulin secretion and glucose excursion ? in a sex-dependent manner ? without alterations in insulin sensitivity, body composition and energy expenditure. These data prompted us to determine the molecular foundation of the crosstalk between sensory neurons and pancreatic ? cells under normal and metabolically challenged conditions. First, we will use live-cell imaging of intracellular calcium influx, proteomics and in vitro co-culture systems to delineate the cellular and molecular mechanisms of the sensory neuron-islet crosstalk. We will use in vitro and in vivo models to interrogate the significance of the neuro-islet intercommunication in the well-known sex difference in glucose homeostasis. Second, we will use high-throughput RNA deep sequencing approach to identify vagal and spinal sensory-derived neuropeptides and growth factors modulating adaptive ?-cell expansion and activity in insulin-resistant states. High-resolution imaging modality (PanCLARITY) will be used to map with accuracy the interactions between pancreatic ? cells and the newly identified sensory neuronal markers. Finally, we will use in vitro and in vivo models to define the role and mechanism of action of novel sensory-derived signaling molecules in proliferation and function of mouse and human ? cells. Together, these studies will unravel the molecular foundation of the unique interactions between afferent neurons and islet ? cells and will provide high-value biological data to design neuropharmacology- and neuromodulation-based strategies to enhance functional ?-cell mass in patients with diabetes.